This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Environmental factors and neurotoxins have been shown to have a profound effect on the complex calcium (Ca2+) signaling mechanism of the cell. We will develop a Comprehensive Model with Biphasic Regulation (CoMBRe) of the IP3 receptor (IP3R) of the endoplasmatic reticulum (ER) by cytosolic [Ca2+] and IP3.The model will be based on a "combined" model assembled from a G protein-coupled receptor (GPCR) model and a Ca2+-induced Ca2+ release (CICR) based model. Both environmental and internal noise are known to have impact on the Ca2+ dynamics through a mechanism known as stochastic resonance (SR). If the Ca2+ dynamics exhibits SR, an optimally chosen Gaussian distributed white noise with zero average can facilitate Ca2+ signal propagation in a sub-threshold parameter region, however, deviation from the optimal value increases the signal degradation which is a fingerprint of SR. Random fluctuations of key dynamical variables and bifurcation parameters along with the circumstances causing noise to corrupt the frequency-encoded Ca2+ signal will be investigated. We will also develop a two-cell model for Ca2+ -dependent neurotransmitter release and subsequent signal transmission. The GPCR initiated signal transmission is triggered by an artificial agonist signal in the first cell;however, the oscillating concentration of the released neurotransmitter from the first cell serves as an actual trigger (agonist) for the second cell mimicking a true model of the communication between cells. The CoMBRe model will be modified to account for the Ca2+-dependent activation of synaptotagmin and SNARE proteins, which are intimately involved in the release of neurotransmitters.